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2015 Research Highlights: Working in Reverse To Assist Pain Drug Development

Researchers began with an observation in humans, applied the observa-tion to mice to learn more, and are using their newfound knowledge to develop better pain treatments. Image credit: mnsanthoshkumar/123RF Stock Photo.

People often wonder, why have recent advances in biomedical research not yielded new drug treatments for pain? The answers are complex, but researchers think one reason is that results from experiments first performed in animals, where most early research begins, don’t always apply to humans as one would like. One route around that pitfall is to work in reverse: begin with observations in human patients, apply those observations to animals to learn more about how the pain system works and how to modulate it with drugs, and, finally, use that newfound knowledge to develop drugs to treat people with chronic pain. That was the strategy employed in research led by Michael Costigan and Clifford Woolf from Boston Children’s Hospital and Harvard University Medical School, US. Indeed, based on findings from human genetics, the investigators developed a compound that relieved pain in animals, and they believe a similar agent can be developed to help people suffering from chronic pain.

In 2006, Costigan, Woolf, and others described a genetic variant found in about 15% of people that seemed to protect them from developing chronic pain after having surgery to remove discs from between the spinal vertebrae. The protection arose from a variation in the gene for an enzyme called GCH1. In turn, GCH1 helps make a molecule called BH4. BH4 is an ingredient in the recipe for neurotransmitters, the chemical signals that nerve cells use to talk to one another.

In the new study, published June 17 in the journal Neuron, the investigators used genetically engineered mice in which they could control when and where GCH1 is made. The experiments confirmed their suspicion that BH4 contributes to pain states, and that it was produced not only by nerve cells but also by immune cells that infiltrate injured nerves.

Once the role of BH4 was clear, the researchers wanted to use a drug to reduce BH4 production, in hopes it would reduce pain in the animals. But because GCH1 and BH4 are so crucial for making neurotransmitters, the researchers knew that they could not block GCH1 activity altogether—that would cause very undesirable side effects. Instead, they considered all the enzymes that are involved in making BH4 and took aim at one called sepiapterin reductase (SPR). Blocking SPR would still allow some BH4 to be made, thereby avoiding a crash in neurotransmitter production.

Consequently, the researchers designed a new drug called SPRi3 to block SPR. SPRi3 reduced levels of BH4 and reduced pain sensitivity in mouse models of neuropathic and inflammatory pain—and without noticeable side effects (see figure). The findings suggest that a similar drug might also safely quell pain in humans. A company co-founded by Woolf, called Quartet Medicine, is now working to develop agents that will safely reduce BH4 levels in people and relieve their pain.

Reverse-engineering: The researchers started with a biochemical pathway known to be important for pain in humans. Then, they used mouse models to understand the pathway in more detail and to design potential new ways to modulate it with drugs. The ultimate goal is to develop those drugs into new therapeutic agents that can be used safely in human patients. Image and caption provided courtesy of Alban Latremoliere.

By starting with a human genetic condition and working in reverse, the team found a viable new molecular target for pain-relieving medications that have great potential to work in people. “This is a blueprint of the kind of project that drug companies would want to pursue,” said Nick Andrews of Harvard Medical School and Children’s Hospital Boston, and a co-author on the paper. —Stephani Sutherland

To read about the research in more detail, see the related Pain Research Forum news story here.

Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance journalist in Southern California. Find her at StephaniSutherland.com or on Twitter @SutherlandPhD

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